In the context of a clinical trial strategy seeking to identify agents that could overcome or circumvent multidrug resistance, my laboratory identified the histone deacetylase inhibitor depsipeptide as an agent in preclinical development and a substrate for Pgp-mediated efflux. Because depsipeptide is avidly transported by Pgp, and because it induces MDR-1 in the constellation of genes altered by histone acetylation, we thought it would fail in clinical development without the addition of a Pgp modulator. In the absence of Pgp, depsipeptide is active in the nanomolar range, whereas other HDAC inhibitors are less potent. Overexpression of Pgp renders cells highly resistant to depsipeptide. To prevent Pgp-mediated resistance to this agent, we reasoned that a Pgp inhibitor should be added early in clinical development. However, the agent had to be evaluated alone in the Phase I setting, and it was there that we made the serendipitous discovery that depsipeptide was highly effective in subsets of T cell lymphoma. While we have continued to be interested in our original strategy of preventing the emergence of resistance to this agent, we have pursued the use of depsipeptide as an orphan drug in T cell lymphoma, using both laboratory and clinical strategies.Our clinical trial for cutaneous and peripheral T cell lymphoma has enrolled 80 patients to date, divided into 4 cohorts. Cohort 1 includes patients with cutaneous T cell lymphoma with fewer than 2 systemic chemotherapy regimens in prior therapy. Responses in this cohort have remained at 50% with over 20 patients enrolled. These responses are at times dramatic and have been very durable. As examples, one patient has received therapy for over 3 years, remaining in a partial remission. Another patient remains in complete remission off of therapy for over 1 year. Slow accrual to this trial, despite recognition of the activity of the agent led us to invite other sites to participate in the trial. Five sites were added in 2002 and we recently received IRB approval for an additional 15 sites to be added. Financial limitations, primarily related to the extensive cardiac monitoring required have hindered activation and accrual at many of these sites. The recent licensing of the agent from Fujisawa Pharmaceuticals to Gloucester Pharmaceuticals and approval of orphan drug status from the FDA should provide an opportunity for increased support of this trial. NCI CTEP and our Cancer Therapeutics Branch have largely pushed the development of this agent alone during a period in which Fujisawa Pharmaceuticals debated the relative merits of becoming involved in an oncology development platform. The findings in this trial were sufficiently convincing that Gloucester Pharmaceuticals has opened a separate trial with the aim of bringing results from 100 patients to the FDA for an NDA. We have added a 5th stratum to the trial to confirm the responses in Cohort 1. Roughly 50 patients will be accrued to this stratum and the results will be presented to the FDA in confirmation of the company's trial. We hope that both trials will be completed in 1 year. Responses with PTCL are also durable and the company has begun discussions with the FDA regarding a development plan for that indication. The trial has a major second objective in addition to proving efficacy in the various histologies. That is confirmation of the safety of the agent. EKG abnormalities have been noted following treatment and a great deal of effort has gone into demonstrating the lack of myocardial damage associated with administration of this agent. One final concern is under evaluation -- in clinical trials sponsored by CTEP across the nation there have been 6 unexpected deaths associated with depsipeptide among over 400 patients treated. While most of these patients had severe underlying cardiac disease, the potential contribution of depsipeptide treatment to these events is under study.